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The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.

Background: The chronic lymphocytic leukemia (CLL) tumor microenvironment (TME) is laden with hyporesponsive T-cells that permit disease persistence. Yet, redundant TME immunosuppressive mechanisms and epigenetic maintenance of T-cell exhaustion limit the efficacy of T-cell targeted therapies in CLL. Bromodomain and extra-terminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T-cell function and differentiation. We hypothesize that blocking BET protein function can reverse T-cell exhaustion to yield durable tumor elimination in CLL. Methods: WT C57BL/6 mice were engrafted with Eμ-TCL1 spleen-derived lymphocytes, then treated daily with the novel pan-BET inhibitor, OPN-51107 (OPN5; 20mg/kg PO) for up to 4 weeks. Splenic gene expression was evaluated with the NanoString PanCancer iO360 panel. T-cell differentiation status, immune inhibitory receptor (IR) expression, proliferation (72 h ex vivo α-CD3/α-CD28 stimulation), and cytokine production (6 h ex vivo PMA/ionomycin stimulation) was measured via flow cytometry. CLL patient and healthy donor PBMCs were used for validation studies and to assess T-cell transcription factor (TF) expression via flow cytometry. Evaluation of BRD4 occupancy at select T-cell TFs via ChIP qPCR is ongoing. Results: OPN5 significantly increased cytotoxic cell signatures and reduced exhaustion-associated cell signatures in leukemic mice through inhibition of T-cell exhaustion signaling, as well as activation of Th1, natural killer cell, and IL-7 signaling pathways. Correspondingly, T-cells from OPN5-treated mice demonstrated greater ex vivo proliferative capacity and effector response to stimuli. A greater proportion of CD8+ T-cells from OPN5-treated mice were classified as naïve, and OPN5 significantly reduced KLRG1 expression on antigen-experienced CD8+ T-cells. Importantly, OPN5 curtailed IR co-expression (PD-1, PD-L1, VISTA, CD244, CD160, and LAG3) on splenic T-cells. These findings were confirmed with primary CLL cells ex vivo. OPN5 also impaired expression of terminal differentiation-associated TFs in CLL patient-derived T-cells, enriching for a TCF1+ progenitor T-cell population. While BTK inhibitors are known to similarly improve T-cell function in CLL, ibrutinib treatment was inadequate to revert CLL T-cell terminal differentiation. Future ATAC-sequencing analysis will inform how BET inhibition alleviates exhaustion-associated chromatin organization in CLL T-cells. Conclusion: BET inhibition dismantles immunosuppressive mechanisms in the CLL TME, alleviating CLL-induced T-cell dysfunction and terminal differentiation. These findings suggest that BET inhibition may be a useful component of combination strategies for the treatment of CLL to yield lasting anti-cancer immune memory and prevent relapsed/refractory disease. Citation Format: Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Christopher R. D'Angelo, Avyakta Kallam, Matthew A. Lunning, Gregory Bociek, Julie M. Vose, Ben Powell, Gideon Bollag, Dalia El-Gamal. BET inhibition alleviates T-cell dysfunction in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6396.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

T cell lymphomas are a heterogeneous group, with varying incidences, geographic patterns, and risk factors. Although until recently approached in a manner similar to B cell lymphomas, the treatment outcomes are poor and this disease is characterized by high relapse rates. The treatment advances in PTCL have been slow compared to B cell lymphomas. The outcomes of patients who progress following stem cell transplantation are worse.This review focuses on the novel targeted agents that are approved and/or are under investigation for patients with relapsed/refractory PTCL. We conducted an electronic literature search of the studies using PubMed, clincaltrials.gov, MEDLINE, using the key words 'PTCL,' 'second line therapy,' and 'targeted agents.' Studies published before January 2020 were included in the search criteria.Development of newer therapies such as HDAC inhibitors and kinases are promising new agents with activity in relapsed/refractory PTCL. Combination therapy using novel agents may be the future for treatment of PTCL. Therapies in the next few years may take a more personalized approach taking into consideration not just the histology, but also the epigenomic landscape.

Adoptive cellular immunotherapy with anti CD19 chimeric antigen receptor (CAR)-T cell has changed the treatment landscape in relapsed/refractory B cell lymphomas. They have emerged as effective therapy in patients with multiple relapsed/refractory disease, capable of sustaining durable remissions. Two CAR-T cell products (axicabtagene ciloleucel and tisagenlecleucel) are currently approved by the United States Food and Drug Administration. A third anti CD19 CAR-T cell, lisocabtagene ciloleucel is currently being evaluated in large clinical trials and may also be United States Food and Drug Administration-approved soon. CAR-T cell-related toxicities, including infections, cytokine release syndrome, and neurotoxicity are potential complications of therapy. With increasing use of CAR-T cells, the mechanism of toxicities and mitigation strategies needs to be developed. Additionally, reasons for CAR-T cell failure and progression following this therapy needs to be further studied. We describe the recent developments in this field, with emphasis on the complications of therapy and factors contributing to toxicities, efficacy, and resistance. We also describe the ongoing research in this field and the newer CAR-T cell constructs that are being developed to counter the challenges that have been identified in this field.

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m

Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccine A 48-year-old woman presented with a 3-day history of fatigue and abdominal pain 2 weeks after receiving the Ad26.COV2.S vaccine. She had a low...

Breast cancer–related lymphedema (BCRL) is a potentially debilitating and often irreversible complication of breast cancer treatment. Risk of BCRL is proportional to the extent of axillary surgery and radiation. Other risk factors include obesity and infections. Given the 5-year survival rate of 90% and its potential impact on the quality of life of survivors of breast cancer, BCRL has become a significant financial burden on the health care system. Minimizing axillary surgery and radiation has been proven to reduce the risk of BCRL. Comprehensive multidisciplinary assessment at the time of initial diagnosis; early referral to physical therapy after surgery; and patient education regarding weight loss, skin, and nail care are cornerstones of the management of early-stage lymphedema. End-stage lymphedema may benefit from referral to a plastic surgeon specializing in lymphedema surgery. In this review, we attempt to review the incidence, risk factors, staging, prevention, and management of this complication of breast cancer treatment. We also describe our multidisciplinary approach for the prevention of this complication at the time of initial diagnosis.

Richter’s transformation (RT) is a rare complication arising in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is associated with an overall dismal outcome. The rarity of this entity poses many challenges in understanding its biology and outcomes seen and the optimal treatment approach. We utilized the SEER (Surveillance, Epidemiology and End Results) database to identify patients diagnosed with CLL/SLL between 2000 and 2016 and subsequently had a diagnosis of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL), thus capturing those who experienced an RT event. We compared the outcomes of those patients to those of patients in the database diagnosed with DLBCL without a preceding CLL/SLL diagnosis. We identified 530 patients who developed RT out of 74,116 patients diagnosed with CLL/SLL in the specified period. The median age at RT diagnosis was 66 years, and the median time from CLL/SLL diagnosis to RT development was roughly 4 years. Patients with RT had a dismal outcome with median overall survival of 10 months. We identified advanced Ann Arbor stage (III/IV) and prior treatment for CLL as predictors of worse outcome in patients with RT. Our study represents the largest dataset of patients with CLL/SLL and RT and adds to the existing literature indicating the poor outcomes for those patients.

Primary central nervous system post-transplant lymphoproliferative disorders (CNS-PTLD) are often high grade lymphomas, with an aggressive clinical course and poor prognosis. Underlying iatrogenic immunosuppression and the risk of graft rejection makes CNS- PTLD a unique entity and challenging to treat. High dose methotrexate and rituximab-based regimens have been most commonly used to treat CNS-PTLD. Treatment of patients who are methotrexate ineligible/ refractory is not well defined. Ibrutinib, a Bruton’s tyrosine kinase inhibitor is a promising treatment for CNS-PTLD due to its ability to cross the blood brain barrier and target the B-cell receptor signaling pathway. We describe a patient with refractory CNS-PTLD who attained a complete response with Ibrutinib and has remained in remission for more than 20 months.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Hodgkin's lymphoma (HL) is largely a curable disease with excellent prognosis. The standard of care in patients with relapsed disease has been to try salvage chemotherapy followed by an autologous stem cell transplantation (ASCT). Managing the patients who relapse after ASCT, is challenging. With the approval of targeted therapies such as PD-1 inhibitors, brentuximab vedotin, the outcomes have improved greatly. Areas covered: This review summarizes the current data available on the newer therapies as well as the present strategies used to treat patients with relapsed HL after an autologous stem cell transplantation. Expert commentary: The approval of brentuximab vedotin and PD-L1 inhibitors has ushered in a new era of targeted therapy in HL. There are currently several targeted therapies under investigation, particularly in the setting of relapsed disease. The current challenges faced are how best to integrate these newer therapies into the existing treatment regimens, finding a right combination with minimal toxicities, role of allogenic transplant in the era of targeted therapy.

Background: Mcl-1 is an anti-apoptotic protein in the Bcl-2 family that contributes to the pathophysiology of certain B-cell malignancies and AML. Dependence on Mcl-1 is associated with poor prognosis, and increased Mcl-1 levels is a common mechanism of resistance to venetoclax. Voruciclib (VORU), a potent oral CDK9 inhibitor (Ki Methods: Pts with relapsed B-cell lymphoma, chronic lymphocytic leukemia (CLL), or AML were eligible if age ≥18 years, ECOG performance status ≤1, disease progression after failure of standard therapies, adequate hepatic and renal function, and no prior CDK9 therapy. Dose escalation started at 50 mg, followed a 3+3 design, and DLTs were assessed in Cycle 1. Initially VORU was administered once daily continuously in a 28-day cycle (Group I). After 2 DLTs were observed at 100 mg, administration was changed to once daily on days 1 to 14 in a 28-day cycle (Group II), patients with prior allogeneic transplant were excluded, and dose escalation (100, 150, 200 mg) proceeded in separate cohorts for AML and B-cell malignancies. Disease response was assessed by the Lugano, iwCLL, and 2017 ELN criteria. Results: To date 28 pts have been enrolled: 14 AML, 7 diffuse large B-cell lymphoma (DLBCL), 3 follicular lymphoma (FL), 2 CLL and 2 mantle cell lymphoma. Group I enrolled 16 pts, 8 each at 50 mg and 100 mg. Group II enrolled 12 pts, 10 with AML administered VORU at 100, 150 or 200 mg and 2 pts with B-cell malignancies administered VORU at 100 mg. Dose escalation in AML is completed. Median age was 71 years (range 40-90) and 54% of pts were male. Pts were generally heavily pretreated, with a median of 3 prior therapies (range 1-8). Median number of VORU cycles administered was 2 (range 1-4). Drug-related serious adverse events (SAEs) were reported in Group I only and consisted of 2 DLT of Gr 3 pneumonitis at 100 mg, both in AML pts treated with allogeneic transplant followed by GVHD in the preceding 12 months, one of whom also had a concurrent Gr 3 differentiation syndrome (DS), and 1 SAE not meeting DLT criteria, a Gr 3 hypoxemic respiratory failure in Cycle 4 in a pt with DLBCL at 50 mg. One AML pt developed ischemic bowel thought to be due to disease progression. Symptoms consistent with DS were observed in 4 AML pts. In Group II, no DLTs have been observed to date and there were no Gr 3-5 drug-related adverse events reported. There is no evidence of significant drug-related neutropenia in pts with B-cell malignancies. To date, in Groups I and II combined, 1 AML pt achieved a morphologic leukemia-free state, 2 AML pts achieved stable disease (SD), and 3 pts with B-cell malignancies had a best response of SD, including 1 FL pt who achieved a 42% reduction in SPD, and 1 CLL pt with relapsed disease after chemoimmunotherapy, venetoclax, and ibrutinib who had stable blood counts. Conclusions: VORU at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle was well tolerated with no DLTs observed. Consistent with the phase 1 studies in solid tumors, no significant myelosuppression was seen in pts with B-cell malignancies. The safety profile does not indicate overlapping toxicities with venetoclax. Disease stabilization was observed in heavily pretreated pts and differentiation syndrome was observed in AML indicating biologic activity. Enrollment at 200 mg will continue in an expansion cohort in AML. A forthcoming protocol amendment will evaluate VORU in combination with venetoclax in pts with relapsed AML to exploit the dual inhibition of Bcl-2 and Mcl-1. Disclosures Konopleva: Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Genentech: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; TG Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding; LOXO: Research Funding; AstraZeneca: Research Funding; MEI Pharma: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; Novartis: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Curis, Inc: Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Abbvie: Consultancy; Aptevo Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Velos Bio: Research Funding; Millenium/Takeda: Research Funding. Diefenbach: Celgene: Research Funding; Trillium: Research Funding; IMab: Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; IGM Biosciences: Research Funding; MEI: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding. Al Malki: Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Abedin: Pfizer: Research Funding; Amgen: Honoraria; Helsinn: Research Funding; Astellas Pharma Inc.: Research Funding; Agios: Honoraria; Actinium: Research Funding; AltruBio: Research Funding. Ghalie: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Davids: Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Vorucicilb is an investigational CDK inhibitor being evaluated in patients with hematologic malignancies, specifically relapsed AML and B-cell malignancies. The abstract submitted to ASH 2021 reports the results of the completed dose escalation portion of a phase 1 study.

Introduction : Chronic Lymphocytic Leukemia (CLL) is characterized by the clonal expansion of mature CD19+/CD5+ lymphocytes in the peripheral blood and secondary lymphoid organs. The accumulation of B-CLL cells yields profound immune defects in the CLL tumor microenvironment (TME), promoting evasion of immune surveillance that contributes to tumor persistence and thus relapsed/refractory disease. The bromodomain and extra-terminal domain (BET) family of proteins are epigenetic readers that bind acetylated histone residues to regulate transcription of numerous genes involved in critical CLL protumor pathways. Of the BET family proteins, BRD4 is overexpressed in CLL and highly enriched at super-enhancers of genes that regulate CLL-TME interactions such as B cell receptor pathway components, chemokine/cytokine receptors, and immune checkpoint molecules. Pan BET inhibitors (BET-i), such as PLX51107 (Plexxikon Inc.) significantly improve survival in aggressive CLL murine models. Here we demonstrate that blocking BRD4 function with PLX51107 (PLX5) can alleviate the inherent immune defects observed in CLL, hence reducing B-CLL induced T cell dysfunction and allowing for robust B-CLL cell elimination. This therapeutic strategy may be vital in overcoming frequent drug resistance and/or bolstering the anti-tumor effect of current CLL therapies. Methods : Primary leukemic B cells were isolated from the peripheral blood of CLL patients and co-cultured with healthy donor T cells to evaluate the effect of PLX5 (0.1-0.5μM) on CLL-induced T cell immunosuppression ex vivo via an array of flow cytometry assays. T cell proliferation was assessed using CFSE after 96 h co-culture with α-CD3/α-CD28 stimulation. Effector cytokine production was evaluated after 48 h co-culture in the presence of PMA/ionomycin (final 6 h) and brefeldin A (final 5 h). Immune inhibitory molecule surface expression was measured following 48 h co-culture with α-CD3/α-CD28 stimulation. To further validate our ex vivo findings, the E μ-TCL1 adoptive transfer model was used. Once disease onset was confirmed in recipient WT B6 mice (>10% CD45+/CD19+/CD5+ peripheral blood lymphocytes), mice were randomized to receive either PLX5 (20 mg/kg) or vehicle (VEH) equivalent daily by oral gavage for 4 weeks. Following treatment, mouse spleens were processed to evaluate exhaustion marker expression, T cell proliferation (CellTrace™ Violet, 72 h a-CD3/α-CD28 stimulation ex-vivo), and T-cell effector function (ex-vivo mitogenic stimulation, 6 h). Results : T cell proliferation indices were reduced following ex vivo co-culture with primary B-CLL cells (mean ± SEM for T cells vs. co-culture, 2.0 ± 0.13 vs. 1.57 ± 0.05; P Conclusion : Epigenetic-targeted therapies such as BET-i have the potential to alleviate CLL-induced T cell dysfunction while eliminating B-CLL cells and preventing tumor expansion. Future profiling studies are pending to further illuminate how BET proteins regulate immune function in CLL. Figure 1 Figure 1. Disclosures Lunning: AstraZeneca: Consultancy; Legend: Consultancy; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Myeloid Therapeutics: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Daiichi-Sankyo: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite, a Gilead Company: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Powell: Plexxikon Inc.: Current Employment.

Introduction: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including hematological malignancies. Zilovertamab vedotin (MK-2140) is an antibody -drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE). Preclinical evidence demonstrated the cytotoxicity of zilovertamab vedotin in hematologic cell lines. This first human phase 1 dose escalation study (NCT03833180) evaluated the safety and efficacy of zilovertamab vedotin at various doses in patients with relapsed/refractory hematologic malignancies. Methods: Eligible patients aged ≥18 years with an Eastern Cooperative Oncology Group Performance Status of 0-2 and histological diagnosis of chronic lymphocytic leukemia/small lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, acute lymphoid leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma (NHL; mantle cell lymphoma [MCL], follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma [DLBCL], Richter transformation, Burkitt lymphoma, and T-cell-NHL) were enrolled. Participants received zilovertamab vedotin intravenously at starting doses of 0.50 mg/kg (up to 2.5 mg/kg) on day 1 every 3 weeks (Q3W) (Schedule 1), 1.0 mg/kg (planned up to 2.25 mg/kg) on day 1 and 8 Q3W (Schedule 2), or 1.0 mg/kg (planned up to 2.25 mg/kg) on days 1, 8, and 15 Q4W (Schedule 3) using an accelerated plus 3+3 dose escalation design. The primary end point was determination of the maximum tolerated dose (MTD). Secondary end points included safety, objective response rate (ORR), and duration of response (DOR). We present data for participants with NHL enrolled in Schedule 1. Results: A total of 51 patients were enrolled in Schedule 1 (starting dose 0.5 [n=1], 1.00 [n=3], 1.50 [n=3], 2.00 [n=3], 2.25 [n=11], or 2.50 [n=30] mg/kg) as of the data cutoff of May 18, 2021. Median (range) age of patients was 70 (44-91) years, 54.9% of patients were male, 49.0% had an ECOG PS of 0, and 41/51 (80%) were diagnosed with NHL; 13/51 (25.5%) were diagnosed with DLBCL and 17/51 (33.3%) were diagnosed with MCL. Enrollment in Schedules 2 and 3 is currently ongoing. The MTD for Schedule 1 was determined to be 2.5 mg/kg. Any-cause adverse events (AEs) occurred in 48 patients (94.1%), most commonly (≥30%) nausea (45.1%), fatigue (45.1%), peripheral neuropathy (41.2%), diarrhea (37.3%), dizziness (35.3%), and neutrophil count decrease (33.3%). Grade ≥3 AEs occurred in 33 (64.7%) patients, most commonly (≥5%) neutrophil count decrease (29.4%), hemoglobin decrease (15.7%), febrile neutropenia (7.8%), peripheral neuropathy (7.8%), platelet count decrease (7.8%), diarrhea (5.9%), lipase increase (5.9%), and pneumonia (5.9%). One patient died due to acute respiratory failure; however, it was not considered treatment-related by the investigator. A total of 7 (13.7%) patients permanently discontinued due to an AE and 18 (35.3%) had treatment interrupted or reduced due to an AE. Treatment-related AEs occurred in 36 patients (70.6%), most commonly (≥20%) peripheral neuropathy (41.2%), fatigue (37.3%), neutrophil count decrease (29.4%), nausea (27.5%), and diarrhea (21.6%); 24 patients (47.1%) experienced a grade ≥3 treatment-related AE. For Schedule 1, ORR was 36.6% (15/41 [95% CI: 22.1%-53.1%]) among all participants with NHL, with 5 having a complete response (CR) and 10 having a partial response (PR). ORR was 38.5% (95% CI: 13.9%-68.4%) for the 13 patients in the NHL group who had DLBCL; 3 patients had a CR and 2 patients had a PR. ORR was 52.9% (95% CI: 27.8%-77.0%) for the 17 patients in the NHL group who had MCL; 2 patients had a CR and 7 patients had a PR. Median (range) DOR was 7.8 months (2.1-17.6+ months) among all participants in Schedule 1 with NHL who achieved a response. Conclusion: These data suggest that targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in patients with relapsed/refractory NHL. Disclosures Wang: Anticancer Association: Honoraria; Dava Oncology: Honoraria; BioInvent: Research Funding; Bayer Healthcare: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Lilly: Research Funding; Scripps: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Research Funding; CAHON: Honoraria; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Genentech: Consultancy; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; OMI: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Chinese Medical Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; BGICS: Honoraria; CStone: Consultancy; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Mei: Janssen: Honoraria; EUSA: Honoraria; Sanofi-Genzyme: Honoraria; Morphosys: Honoraria; TG Therapeutics: Other: Institution: Research Grant/Funding; Epizyme: Other: Institution: Research Grant/Funding; BMS: Other: Institution: Research Grant/Funding; Beigene: Other: Institution: Research Grant/Funding; Incyte: Other: Institution: Research Grant/Funding. Barr: Beigene: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy. Furman: Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Loxo Oncology: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria; Sunesis: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Morphosys: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sunesis Pharmaceuticals: Research Funding; Juno Pharmaceuticals: Consultancy; MEI Pharma: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Millenium/Takeda: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Aptevo Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding; Velos Bio: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Curis, Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Zhu: Merck & Co., Inc.: Current Employment. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Spurgeon: Ionis: Other: Institution: Research Grant/Funding; Gilead Sciences: Other: Institution: Research Grant/Funding; Bristol Myers Squibb: Other: Institution: Research Grant/Funding; BeiGene: Other: Institution: Research Grant/Funding; AstraZeneca: Other: Institution: Research Grant/Funding; Acerta Pharma: Other: Institution: Research Grant/Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; Karyopharm: Consultancy; Velos Bio: Consultancy, Other: Institution: Research Grant/Funding; Merck & Co., Inc.: Other: Institution: Research Grant/Funding; Fred Hutchinson Cancer Research Center: Other: Data Safety Monitoring Board.

Background: Acute Lymphoblastic Leukemia (ALL) outcomes have significantly improved over time with multi-agent chemotherapy, and the addition of asparaginase (ASP) has demonstrated the ability to prolong overall survival. ASP has multiple toxicities, and it remains a challenge to manage them safely, particularly coagulopathy and thrombosis (30-40% based on historical studies). The best prophylactic anticoagulation strategy in patients with acute leukemias, particularly ALL with asparaginase use, remains unclear due to severe coexisting thrombocytopenia and coagulopathy. Though the current guidelines recommend using Antithrombin (AT) replacement or low molecular weight heparin (LMWH) for thrombosis prophylaxis, the evidence is weak with concerns of thrombosis (Blood (2020) 136 (3): 328-338) with the use of fibrinogen concentrates(cryoprecipitate) and limited efficacy data with AT replacement and unfractionated heparin (UFH) for thrombosis prophylaxis. Due to potential "resistance" to LMWH and UFH from acquired AT deficiency with ASP use, our institution in 2017 has adopted the use of the direct Xa inhibitor, Apixaban for thrombosis prophyalxis. We report the safety and effectiveness of Apixaban for thrombosis prophylaxis with ASP. Methods: In this retrospective study, we reviewed the data on 20 patients treated with ASP between 2017-2020. Thrombosis prophylaxis was instituted with Apixaban 2.5 mg PO Q 12 hourly for three weeks along with cryoprecipitate as needed for bleeding or fibrinogen levels Results: Among the 20 patients treated during this period, 18 (90%) had ALL, and 2(10%) had NK/T cell lymphoma. Of the patients with ALL, 67% had high risk and 33% with standard-risk ALL. The median age of this cohort was 29.5 years (range: 19-63 years), 80% were males, 70% white, 30% were Latino or Hispanic, median body mass index-BMI of 30.2 kg/m 2(19.4-40.7 kg/m 2) and 65% were non-smokers. The median baseline AT activity was 107% (79-221%), 95% used concurrent corticosteroids (65%- Prednisone, and 30% used Dexamethasone). The most common induction treatment was CALGB 10403 (55%). Of the total, 95% received pegylated ASP, and only one patient received Erwinia ASP due to prior history of anaphylaxis. The major toxicities attributed to ASP included 5% grade II and 15% grade III-IV aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, 20% had bilirubin elevation, 10% developed grade III-IV acute pancreatitis, and 5% developed severe hypertriglyceridemia needing aphaeresis. Two patients (10%) developed thrombosis [catheter associated deep venous thrombosis (DVT) and one patient with lower extremity proximal DVT] within 4 weeks of use of ASP, with one of the two patients (5%) developing (lower extremity proximal DVT) while on being off anticoagulation due to bleeding. Major bleeding or CRNMB developed in 5% (spontaneous splenic rupture from ALL leading to hemorrhagic shock). The median number of cryoprecipitate units used per patient during weeks 1,2,3, and 4 was 5(0-35), 5(0-40), 5(0-15), 7.5(0-15), respectively; No patients received fresh frozen plasma or AT concentrates. Conclusions: With the use of Apixaban prophylaxis, the incidence of thrombosis was 10% within four weeks from ASP and 5% while on anticoagulation. The incidence of major bleeding or CRNMB was 5%. Hypofibrinogenemia, acquired AT deficiency due to ASP, was seen between days 7-21 after using ASP (figure 1 & 2) and recovered subsequently. This study demonstrates initial evidence of the safety and efficacy of Apixaban for thrombosis prophylaxis and cryoprecipitate infusions in patients treated with ASP. Figure 1 Figure 1. Disclosures Gundabolu: Samus Therapeutics: Research Funding; Pfizer: Research Funding; BioMarin Pharmaceuticals: Consultancy; Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy. Bhatt: Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Kyowa Kirin: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Legend: Consultancy; Kite, a Gilead Company: Consultancy; Verastem: Consultancy; Acrotech: Consultancy; Karyopharm: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Morphosys: Consultancy. Baljevic: BMS/Celgene: Consultancy; Oncopeptides: Other: Advisory Board; Janssen Research: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Exelixis: Research Funding. Ganti: Merck: Research Funding; Apexigen: Research Funding; Nektar: Research Funding; Top Alliance Biosceinces: Research Funding; Lovance: Research Funding; Novartis: Research Funding; WindMil Therapeitucs: Research Funding; Takeda: Research Funding; Flagship Biosciences: Consultancy; AstraZeneca: Consultancy, Other: Advisory Board; Mirati Therapeutics: Consultancy, Other: Advisory Board; G1 Therapeutics: Consultancy, Other: Advisory Board; Blueprint Medicines: Consultancy, Other: Advisory Board; Cardinal Health: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board; YMabS Therapeutics: Other: DSMC Chair.

Introduction Relapses involving the central nervous system (CNSrel) occur in ~5% of patients (pts) with aggressive non-Hodgkin lymphoma (NHL) in the rituximab era (Ghose et al, Clin LML 2015) with rates exceeding 10% in high risk groups (Villa et al, Ann Onc 2010; Schmitz et al, JCO 2016). CNSrel are generally thought to occur in the first 4-6 months from diagnosis. Prophylaxis (PPx) administration, route, and frequency are not standardized, and the impact of PPx on CNSrel risk is incompletely understood. Methods We performed a multicenter retrospective analysis of pts with aggressive NHL (excluding Burkitt's) without known CNS involvement (inv) who received single-route CNS PPx with during front-line (FL) anthracycline-based therapy (tx) from 2013-2019 across 19 US academic institutions. Recipients of chemotherapy for prior CLL or indolent NHL were ineligible. Method, frequency, and outcomes of CNS PPx administration were evaluated, with significance assessed by various statistical methods via two-tailed P Results 1030 patients were identified who met eligibility criteria. Clinical features included median age 61 years (yrs; range 16-86), 40.9% female, ECOG PS 0-1 82.8%, elevated LDH 65.3%, >1 extranodal (EN) site 42.3%, stage 3/4 disease 79.2%. NHL histologies included diffuse large B cell (DLBCL; 75.2%), high grade B cell (16.3%), transformed follicular lymphoma (5.6%) and 3% other; among pts with DLBCL, 46.4% had germinal center (GCB) subtype and 40.5% had non-GCB. 26.2% (n=210) of evaluable pts had double-hit lymphoma (DHL). Among pts with known HIV status, 7.2% (n=65) were HIV-positive. 85.7% had EN inv; common sites included bone (35.4%), liver (13.7%), gastrointestinal (12.7%), lung (11.8%), and marrow (11.5%). FL regimens included RCHOP (45.9%), REPOCH (46.5% total; 79.1% with dose-adjustment), 7.6% other. PPx was given intravenously (IV) in 20% of pts vs 77% intrathecally (IT), over a median 2.9 vs 4.1 doses respectively; see Table 1 for factors associated with PPx route. PPx was generally well-tolerated, with 10.7% PPx-related toxicity reported; see Table 2. CNSrel after FL tx was 5.3% overall without significant difference by PPx route (7% IV vs 5% IT, p=0.178). This lack of difference between PPx routes was observed in all subgroup analyses performed, including by: age, stage, histology, number of EN sites, individual EN site inv, elevated LDH, CNS-IPI, DHL status, HIV status, FL regimen, number of PPx doses. There was no significant difference in anatomic site(s) of CNSrel by PPx route. CNSrel occurred bimodally: 24% by end of FL tx vs 76% delayed (average 2.3 yrs, range 0.4-5.2 yrs). Rates of CNSrel were significantly higher with CNS-IPI high vs moderate risk (8.3 vs 4.1%, p=0.03; Figure 1), elevated LDH (6.9 vs 2.6%, p=0.007) and multiple inv EN sites (7.5% for 2+ vs 4% for 0-1, p=0.01); each additional EN site further increased risk (p=0.03 for trend; Figure 2). Increased CNSrel was noted in pts with testis (13.7 vs 5%, p=0.004) and liver inv (11.1 vs 4.6%, p=0.002) vs those without inv at respective sites. No significant difference was noted at other EN sites, including renal/adrenal (4.8 vs 5.6%, p=0.71), marrow (8.9 vs 5.1%, p=0.09), or lung (8.6 vs 5.1%, p=0.12). All EN site-CNSrel correlations were unchanged when accounting for PPx route. With median follow-up of 2.3 yrs, median PFS and OS for the overall group have not been reached; 2-yr PFS and OS were 70 and 85% respectively. PFS and OS were each predicted by CNS-IPI (p Conclusion Use of single-route ppx demonstrated similar CNSrel vs established outcomes for this population in the rituximab era, with no difference by PPx route. CNSrel remains a rare but devastating complication, with greater risk even after single-route PPx in those with higher EN burden and inv of key EN sites. Disclosures Kahl: Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Spinner:Notable Labs: Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Voorhees:AstraZeneca: Research Funding. Grover:Genentech: Research Funding; Tessa: Consultancy. Huntington:Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Bayer: Consultancy, Honoraria; DTRM: Research Funding; Astrazeneca: Honoraria; AbbVie: Consultancy. Spurgeon:Beigene: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding; Genmab: Research Funding; AstraZeneca: Research Funding; Acerta: Research Funding. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Landsburg:Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Triphase: Research Funding. Kamdar:Roche: Research Funding. Caimi:Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Verastem: Other: Advisory Board; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Celgene: Speakers Bureau. Karmali:Takeda: Research Funding; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Stephens:Pharmacyclics: Consultancy; Innate: Consultancy; Verastem: Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Research Funding; Arqule: Research Funding; Juno: Research Funding; MingSight: Research Funding; Acerta: Research Funding; Beigene: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Khan:Celgene: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Honoraria. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Portell:Bayer: Consultancy; Xencor: Research Funding; BeiGene: Consultancy, Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding.

Background Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) and most common of the clinically indolent NHLs. Although often considered an incurable disease, overall survival has increased significantly with refinement in diagnostic techniques and the addition of rituximab. The course of FL is quite variable and presence of symptoms, organ dysfunction, cytopenias, aggressiveness of tumor are all taken into consideration when deciding individual treatment. In this study, we evaluated a large patient cohort with FL treated over a 35 year period for progression free survival (PFS), overall survival (OS) based on FLIPI score, tumor grade, and treatment regimen and also looked at causes of late failures. Methods We evaluated 1037 patients (pts) from the Nebraska Lymphoma Study Group that were diagnosed with FL between the years of 1983-2020. Descriptive statistics were stratified according to age, histological subtype, treatment regimen, FLIPI category, presence and type of secondary malignancy. PFS was calculated from the time of diagnosis to progression or death and OS was the time from diagnosis to death from any cause. PFS and OS were plotted as Kaplan-Meier curves with statistically significant p Results The median age at diagnosis and treatment was 61 years (yrs, range 17-91). A total of 9.1% were characterized as FLIPI high risk, 37.8% intermediate risk, and 33.6% low risk, 19.5% unavailable. Among the histological grade, 23.1% had FL- grade 1, 30.2% FL-2, 27.3% FL-3A, 2.5 % FL-3B and 16.9 % Composite Lymphoma. Anthracycline + rituximab was given in 24.5% of pts, whereas 43.8% of pts received an anthracycline based regimen without rituximab, 9.8% received rituximab without an anthracycline and 10.6% received neither of these agents. 6.75% (70 pts) were later found to have secondary malignancies of which 11 pts had myelodysplastic syndrome, 10 pts had acute leukemia and 9 pts had lung cancer. With a median follow up of 9.2 yrs and a maximum of 36 yrs, 29.7% (308 pts) had not relapsed. The median PFS across all groups was 4.6 yrs (Fig 1) and OS was 12.1 yrs. Median OS was significantly longer in patients that received rituximab at 16.1 yrs as compared to patients that did not receive rituximab at 9.89 yrs (Fig 2). PFS was 8.6 yrs, 3.6 yrs and 2.1 yrs and OS was 15.1 yrs, 11.7 yrs and 4.9 yrs in FLIPI low, intermediate and high risk groups respectively (p= When pts with FL-3A and FL-3B were grouped together and stratified according to treatment regimen, the group that received anthracycline and rituximab combination has highest PFS and OS at 13.3 yrs and 18.8 yrs (p Among the pts that relapsed/died after 10 years (n=190), the cause of death was relapsed lymphoma in 13.7%, unknown in 55.8%, secondary malignancies in 4.2%, treatment related in 2.6% and not related to disease in 23.7%. A total of 278 pts survived > 10 yrs, and of these pts, 119 (30%) had not relapsed at the last follow up. Conclusion The addition of rituximab to standard anthracycline based chemotherapy has resulted in significant improvements in the PFS and OS rates of FL. These results also support the prognostic value of the FLIPI in patients treated in the rituximab era. Late relapses after 10 yrs from disease can occur, but 11.5% of patients had not relapsed with long term follow up. Secondary malignancies are also an important consideration in the long term survivors. Disclosures Lunning: Acrotech: Consultancy; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Verastem: Consultancy, Honoraria; ADC Therapeutics: Consultancy. Armitage:Trovagene/Cardiff Oncology: Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Ascentage: Consultancy. Vose:Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Seattle Genetics: Research Funding; Allogene: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Wugen: Honoraria; Novartis: Research Funding; Celgene: Honoraria; Incyte: Research Funding; Roche/Genetech: Consultancy, Honoraria, Other; Verastem: Consultancy, Honoraria; Miltenyi Biotec: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.

Introduction: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is physiologically expressed during embryogenesis, largely disappears by birth, but can be reexpressed pathologically in transformed tissues of many hematological and solid cancers. VLS-101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). Methods: This first-in-human, Phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and efficacy of VLS-101 in patients unselected for tumor ROR1 expression who had previously treated chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Richter transformation lymphoma (RTL). VLS-101 was infused over 30 min every 3 wk until cancer progression or intolerable toxicity. After accrual of 1 patient at the first dose level, cohorts were enrolled by 3+3 dose escalation with additional patients accrued and intrapatient dose escalation permitted to refine estimates of maximum tolerated dose and recommended dosing regimen (RDR). Results: 32 patients were enrolled, including 19 males and 13 females with median (range) ages of 70 (54-84) ys; ECOG performance status (n) of 0 (18), 1 (10), or 2 (4); and tumor types (n) of MCL (15), CLL (7), DLBCL (5), FL (3), MZL (1), and RTL (1). Patients had received a median (range) of 4 (1-24) prior systemic therapies including hematopoietic stem cell transplantation (5) and/or chimeric antigen receptor (CAR)-T or -natural killer (NK) cells (6). Among patients with MCL, 15/15 (100%) had received a Bruton tyrosine kinase inhibitor (BTKi), 13/15 (87%) discontinued the BTKi due to progressive disease, and 2/15 (13%) discontinued for atrial fibrillation after 15.6 or 68.5 months of BTKi therapy. Patients (n) by VLS-101 starting dose were 0.5 (1), 1.0 (3), 1.5 (3), 2.25 (11), and 2.5 (14) mg/kg. With intrapatient dose escalation, many patients (n) received a maximum of 2.25 mg/kg (12) or 2.5 mg/kg (17) during VLS-101 therapy (range: 1 to 13 cycles). Cycle 1 DLTs (n/N) by mg/kg dose level were 0.5 (0/1), 1.0 (0/3), 1.5 (0/3), 2.25 (1/11 [9%] Gr 4 neutropenia), and 2.5 (2/14 [14%]; one Gr 4 neutropenia; one Gr 3 diarrhea of uncertain cause). Gr 4 neutropenia occurred in 9/32 (28%) patients; 1/32 (3%) had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. Baseline Gr 1 neuropathy was present in 10/32 (31%) patients. On-study reversible Gr 3 neuropathy occurred in 3/32 (9%) patients; no Gr 4 neuropathy occurred. Except for Gr ≤2 alopecia in 3/32 (9%) patients, other adverse events were not obviously drug-related. Considering all 175 infusions administered, drug-related infusion reactions, vomiting, tumor lysis syndrome, rash, hepatic or renal abnormalities, or QT prolongation were not observed. PK showed changes in ADC and MMAE exposures proportional with VLS-101 dose and a mean ADC half-life of ~2.5 d. PD indicated exposure-dependent ROR1 occupancy on circulating CLL cells. No neutralizing anti-drug antibodies were detected. Objective tumor responses were not seen in patients with other tumor types but were observed in 7/15 (47%) of patients with MCL (4 partial; 3 complete) and in 4/5 (80%) of patients with DLBCL (2 partial; 2 complete). From start of therapy, 6/7 patients with responding MCL have responses ongoing at 35, 38, 45, 47, 50, and 58 wk and 2/4 patients with responding DLBCL have responses ongoing at 23 and 47 wk of follow-up. Conclusions: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS-101 RDR was 2.5 mg/kg every 3 wk. Efficacy results provide clinical proof of concept for targeting ROR1 with VLS-101 and demonstrate durable objective responses in patients with advanced MCL or DLBCL, including those with prior BTKi or cellular therapies. Phase 1-2 studies of VLS-101 monotherapy and combination therapy in patients with hematological cancers and solid tumors are planned. Figure Disclosures Wang: Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Oncternal: Consultancy, Research Funding; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Guidepoint Global: Consultancy; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria. Barrientos:Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Janssen: Honoraria; AstraZeneca: Consultancy. Furman:Verastem: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barr:AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Choi:Genentech: Consultancy; Pharmacyclics/Abbvie: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Rule:Janssen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy. Flanders:VelosBio: Current Employment, Current equity holder in private company. Jessen:VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Riebling:VelosBio: Current Employment, Current equity holder in private company. Graham:Ce3: Current Employment. King:Ce3: Current Employment; VelosBio: Consultancy; AI Therapeutics: Consultancy. Schmidt:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Johnson:Zentalis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current equity holder in publicly-traded company; Neoleukin: Current equity holder in publicly-traded company; Oncternal: Divested equity in a private or publicly-traded company in the past 24 months; Appelis: Divested equity in a private or publicly-traded company in the past 24 months; Acerta: Patents & Royalties; VelosBio: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Miller:Cleveland BioLabs: Consultancy, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Cancer Genetics: Current equity holder in publicly-traded company; Incuron: Consultancy; Zentalis: Consultancy, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; EpiThany: Current equity holder in private company; AstraZeneca: Current equity holder in publicly-traded company; VelosBio: Consultancy, Current Employment, Current equity holder in private company; AI Therapeutics: Consultancy, Current equity holder in private company; Catalys Pacific: Consultancy. Spurgeon:Cardinal Health: Honoraria; VelosBio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Beigene: Research Funding; Verastem: Research Funding.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for the baseline prognostic assessment in these patients. The present study aimed to determine the effect of the treatment facility on the overall survival outcomes in patients with DLBCL stratified by IPI risk groups.The National Cancer Database was used to identify patients with a diagnosis of DLBCL from 2004 to 2015. DLBCL was stratified by the IPI risk score from low- to high-risk disease, and the overall survival of those treated at academic centers was compared with that of those treated at nonacademic centers.Treatment at academic centers was associated with significantly improved overall survival for all patients with DLBCL (108.3 months) compared with those treated at nonacademic centers (74.5 months; P .001). The median survival for patients with high-risk disease treated at academic centers (33.5 months) was more than twice that of high-risk patients treated at nonacademic centers (14.4 months; P .001). The median survival for the other risk categories was similarly improved, although less pronounced in the lower IPI score groups. The long-term overall survival for all patients with DLBCL at academic centers was improved at 5 and 10 years (59% and 43% survival, respectively) compared with those treated at nonacademic centers (51% and 35% survival, respectively; P .001).Patients with DLBCL treated at academic centers demonstrated improved survival compared with those treated at nonacademic centers, especially those with high-risk disease. Further investigations into the factors contributing to such disparities are required to help standardize care and improve outcomes.

Hodgkin lymphoma is a highly curable malignancy, with an excellent prognosis. However, around 10% to 25% of patients will have primary refractory or relapsed disease, despite using risk-adapted strategies. The standard of care for patients with relapsed/refractory Hodgkin lymphoma has been cytoreduction using salvage chemotherapy, followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). Studies have shown that AHSCT produces a durable response rate of 50%, and that patients achieve a complete response with salvage chemotherapy. The outcomes for patients who do not respond to salvage chemotherapy or relapse after an AHSCT have been poor, with a median survival of 25 months. However, with the approval of novel agents over the last decade, the outcomes for patients with relapsed/refractory Hodgkin lymphoma have improved significantly. In this article, we present a case of a patient with relapsed Hodgkin lymphoma who responded to salvage chemotherapy incorporating brentuximab vedotin, a novel agent.

Patients with immune thrombocytopaenia (ITP) have a wide spectrum of disease severity and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidence supports the use of high-dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients; however, the outcomes of such management approach need to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.

With improvement in the cure rates for diffuse large B cell lymphoma, the question of surveillance imaging in patients who achieve complete remission after the initial therapy has become relevant. Some of the clinical practice guidelines recommend surveillance scanning. However, several studies have reported no benefit in overall survival with scans. Moreover, studies have highlighted an increased risk for developing secondary malignancies because of exposure to ionizing radiation from the scans. Different international societies have contrasting guidelines for the role of surveillance computerized tomography scans in patients who achieve complete remission after first-line therapy. Any benefit of surveillance imaging must be balanced by the costs, risk of radiation exposure, and lack of survival benefit. The PubMed platform was searched using relevant keywords for English-language articles with no date restrictions. Search terms were cross-referenced with review articles, and additional articles were identified by manually searching reference lists. Results were reviewed by the authors and selected for inclusion based on relevance. We present a review of this current data available for surveillance imaging in patients with diffuse large B cell lymphoma.

Paraneoplastic syndromes, although rare, have been associated with lymphoproliferative disorders. Hodgkin’s lymphoma (HL) is the most common lymphoid neoplasm known to cause paraneoplastic syndromes. These syndromes can often be the earliest manifestation of the underlying malignancy, and treating the underlying lymphoma can cure the paraneoplastic disease. Paraneoplastic diseases reported in lymphoid malignancies can be broadly classified into hematological, neurological, and dermatological syndromes based on the organ systems that are predominantly involved. In addition, renal and hepatobiliary involvement has also been reported. The pathogenesis of the hematological paraneoplastic conditions primarily involves the production of autoantibodies by the neoplastic lymphocytes, which then subsequently leads to cytopenias. Cytoses are a result of cytokine produced by the neoplasms. The administration of corticosteroids along with chemotherapy for the underlying malignancy is the treatment of choice. Neurological paraneoplastic phenomena have been reported in both HL and non-Hodgkin’s lymphoma (NHL). They are thought to be secondary to an immune-related process that is triggered by the underlying process. Both the central and the peripheral nervous systems can be affected. Often, treatment of the underlying malignancy with chemotherapy can result in reversal of the paraneoplastic syndrome. In peripheral neuropathies, muscle relaxants and analgesics are often used for symptomatic relief. Dermatological manifestations, pemphigus vulgaris in particular, often precedes the malignancy. Renal and hepatobiliary manifestations, although rare, are also associated with lymphomas.

e20024 Background: Richter's transformation (RT) from Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) to a Diffuse Large B-Cell Lymphoma (DLBCL) is a rare complication with an estimated incidence of less than 5% and a poor prognosis based on small retrospective studies. Large studies investigating the natural history and patient outcomes with this entity of DLBCL are lacking, and prospective data on the best treatment option are scarce and limited by rarity of this condition. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) 18 database for patients sequentially diagnosed with CLL/SLL followed by DLBCL from January 2000 to December 2016 with a cutoff latency of 2 months. Data obtained included patient demographics, history of treatment for CLL/SLL, overall survival (OS) after DLBCL diagnosis and latency period between CLL/SLL and DLBCL diagnoses. For comparison, SEER data was obtained for patients with de novo DLBCL and for CLL/SLL patients without RT in the same date range. Survival was estimated by Kaplan Meier method and log rank test was used to compare outcomes. Results: 471 patients who developed RT to DLBCL and 98425 patients with de novo DLBCL were identified. The median time for developing RT to DLBCL was 54 months. Median OS was worse for DLBCL arising from RT compared to de novo DLBCL (64 months versus 10 months, p < 0.0001). In patients with RT to DLBCL, no statistically significant difference in median OS was seen in patients who received treatment for CLL/SLL versus those assigned as No/Unknown treatment status (p = 0.51). In patients with CLL/SLL in the specified time period; median OS was significantly lower for those who developed RT to DLBCL compared to those who did not (91 months versus 100 months, p = 0.0012). Conclusions: DLBCL arising from RT in CLL/SLL patients is not necessarily a late complication. Prognosis is dismal with a trend towards a poor OS in the subset of patients with pretreated CLL/SLL. This large population study correlates with prior reports and highlights the need for prospective data to inform prognosis and treatment decisions.

e19204 Background: Methotrexate (MTX) is used in high doses for the treatment of ALL, lymphoma, and metastatic breast cancer with CNS involvement. To avoid drug accumulation and mitigate toxicities caused by delayed clearance, patients (pts) are usually admitted to the hospital and standard supportive care with IV hydration, urinary alkalization, and leucovorin is provided and adjusted based on daily levels. Historically, a serum methotrexate level ≤ 0.05 µmol/L has been used to declare clearance and an ideal level for discharge based on studies conducted in the 1970s. We conducted a retrospective review in 2018 to identify frequency of supportive dose escalations required with MTX levels > 0.05 µmol/L. In 69 pts, 4 patients demonstrated delayed renal clearance and required supportive care escalations but all occurred at MTX levels > 0.3 µmol/L. This led to a proposed pilot discharge process once MTX was < 0.3 µmol/L to confirm the safety of earlier discharge. Methods: A retrospective chart review of pts with baseline CrCl ≥60 who received HD MTX between 07/2018 – 08/2019. Data collection included diagnosis, MTX discharge level, supportive care at discharge including PO Leucovorin and PO sodium bicarbonate and number of days supply, post-discharge complications (AKI, mucositis, fever, others). Primary outcome was the number of patients who required inpatient or outpatient supportive care for acute complications after being discharged with a methotrexate level ≥ 0.1 µmol/L. Descriptive statistics were used. Results: A total of 41 pts were included. Median age was 55 yrs (32-78), 25% were male. 73% were treated for DLBCL, median dose of MTX was 3500 mg/m2. Median MTX level at the time of discharge was 0.16 µmol/L (0.1-0.3 µmol/L). 12 pts were discharged with PO Leucovorin and 15 pts were discharged with both Leucovorin and PO Sodium bicarbonate with an average of 2 day’s supply. 1 acute complication of neutropenic fever requiring admission for inpatient antibiotics occurred which was felt to be unrelated to MTX level at discharge. Conclusions: This pilot suggests that pts can be safely discharged with MTX levels upto 0.3 µmol/L without acute complications. Results of this study will be used to a develop a standardized protocol outlining criteria for early discharge in select pts with MTX levels < 0.3 µmol/L to reduce length of stay, cost of hospitalization and improve patient satisfaction. [Table: see text]

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has been approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Long-term follow-up of the ZUMA-1 trial demonstrated that 39% of patients who received axicaptogene ciloleucel were progression free at two-years. Objectives CAR-T cell therapy, as a treatment option, has likely been hindered by logistical barriers, including patients' insurance approval/single case agreement (SCA) process and the distance to the CAR-T treatment center from their home. Methods Patient (Pt) information was retrospectively reviewed from our commercial CAR-T cell therapy experience between 1/2018 and 7/2019. Standard patient demographics and disease characteristics were collected. Progression free survival (PFS) and overall survival (OS) time points started with the treating physician's documentation of intent to CAR-T (iCAR-T). Pts were further assessed based on public (Medicare/Medicaid) or private insurance and distance from CAR-T center to home (> or ≤ than 120 miles). Statistical analysis was then completed on the data. Fischer's Exact tests and Mann-Whitney tests were used to compare the patients, while log-rank tests were used to compare Kaplan-Meier Curves. Results A total of 25 pts were reviewed. Four pts had intended to be apheresed for CAR-T but did not reach the apheresis time point. In the entire cohort, the median PFS and OS have not been reached. The median follow-up was 5.5 months (range: 1.5 to 15 months) for those infused with CAR-T. Pts with public insurance (N=7) received CAR-T infusion more quickly (p = 0.0080) than those with private insurance (N=14). However, this did not influence PFS (p = 0.2856) or OS (p = 0.5073) with balanced disease and demographic characteristics other than age 120 miles; N=10 or ≤ 120 miles; N=11) from a patient's home to the CAR-T center did not affect PFS (p = 0.8914) or OS (p = 0.9078). Neither analysis for PFS or OS was significantly altered with the addition of the iCAR-T population. Conclusion In this experience, pts with public insurance appear to proceed from agreement to CAR-T with subsequent CAR-T infusion (Brain to Vein) more quickly, but the time to apheresis does not appear to affect outcome. Also, the distance from the CAR-T cell center does not appear to be a predictor for worse outcomes. Both logistical barriers occurring pre-apheresis warrant further assessment in a larger multicenter experience.

Background: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, key building blocks for RNA and DNA biosynthesis. Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide). Brequinar, a more specific and potent DHODH inhibitor, was evaluated in several phase 1 trials in patients with advanced solid tumors in the 1990s and demonstrated little evidence of antitumor activity; however, patients with hematologic malignancies were not evaluated in those studies. More recent preclinical studies show that cell lines and in vivo models derived from hematologic malignancies are highly sensitive to inhibition of DHODH. AG-636, a novel small molecule DHODH inhibitor, demonstrated strong in vitro and in vivo anti-tumor activity across diverse models of lymphoma and acute leukemia, supporting the evaluation of AG-636 as a treatment for patients with lymphoma and other hematologic malignancies. A phase 1, multicenter, open-label study investigating AG-636 for the treatment of patients with advanced lymphoma began enrollment on May 24, 2019 (NCT03834584). Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-636 and to characterize its dose-limiting toxicities (DLTs) when given to patients with advanced lymphoma. The study includes a dose escalation phase followed by an expansion phase. Approximately 54 adults (42 in the dose escalation phase and 12 in the expansion phase) with advanced lymphoma refractory to standard treatment, will be enrolled at up to 6 centers in the United States. Broad inclusion criteria enable patients with Hodgkin, Diffuse Large B-Cell (DLBCL), Follicular, Peripheral T-Cell, Cutaneous T-Cell, Mantle Cell, and less common subtypes of lymphoma as defined in 2017 by the World Health Organization to enroll. There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy. Patients with active central nervous system disease are excluded. Patients must have an Eastern Cooperative Oncology Group performance status ≤2, an absolute neutrophil count ≥1.0×109/L, a platelet count ≥75×109/L, a serum total bilirubin level ≤1.5×upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels ≤3.0×ULN, and a creatinine clearance ≥30 mL/min (Cockcroft-Gault formula). AG-636 is given as an oral capsule once daily for 2-5 days each week, with 1 cycle of therapy defined as 4 consecutive weeks of treatment. During the dose escalation phase of the study, successive cohorts of patients will be treated with increasing doses of AG-636 to estimate the MTD. The study employs a 2-parameter adaptive Bayesian logistic regression model using escalation with overdose control to guide dose escalation and to estimate the MTD. The MTD is the highest dose that is unlikely ( Disclosures Huntington: Celgene: Consultancy, Research Funding; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy. Basile:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Ulanet:Agios: Employment, Equity Ownership. Xu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yin:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobilia:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria. Leonard:Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy; AstraZeneca: Consultancy. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.

We present a case of a dialysis-dependent end-stage renal disease patient who originally presented with sepsis and later developed heparin-induced thrombocytopenia-related upper extremity deep venous thrombosis that rapidly progressed to phlegmasia. Argatroban, a direct thrombin inhibitor, was initiated without delay. Argatroban restored the venous patency completely but did not reverse his two gangrenous fingers. The patient finally underwent digital amputation. The management of this uncommon, but life-threatening, situation of upper limb phlegmasia cerulea dolens secondary to heparin-induced thrombocytopenia leading to gangrene is discussed in this case report.

Introduction Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is a validated scoring system that assesses the risks of patients (pts) undergoing allogenic stem cell transplant. [Sorror et al. 2005] There has been emerging evidence of its value in risk discussion for pts undergoing autologous stem cell transplantation (ASCT). In a recent large (N=1730) retrospective study in pts with multiple myeloma (MM) or lymphoma, a high-risk HCT-CI was associated with higher rates of orotracheal intubation (OTI), 100-day non-relapsed mortality (NRM), and 1-year mortality. [Berro et al. 2017] Not well studied was disposition of a pt at the time of discharge post-transplant as it relates to HCT-CI risk. This could be an additional useful variable in pts/caregiver discussions pre-ASCT. Herein, we report a retrospective single institution review of our experience as it relates to HCT-CI to post-ASCT outcomes including level of care requirements at time of discharge. Methods We performed a retrospective review of pts with MM or lymphoma who received consolidative ASCT between May 2013 and March 2018. Pt demographic were collected. Pts HCT-CI were collected per defined variables by Sorror et al. Each pt was divided into three cohorts: low risk (HCT-CI score of 0), intermediate risk (HCT-CI score of 1-2), and high risk (HCT-CI ≥ 3). Discharge location was categorized into five dispositions: home with caregiver, home with supplemental care, skilled nursing facility, acute rehab facility, and died during transplant. Results Four hundred sixty-one charts were reviewed. Males were 62.0% of the population with a median age of 58.5. Disease populations were balanced with MM/lymphoma at 48.4%/51.6% respectively. MM pts received melphalan (140 or 200 mm/m2) and lymphomas received BEAM based conditioning. We found no statistical correlation of high-risk HCT-CI patients requiring higher rates of OTI during ASCT (p=0.1066) nor requiring a higher level of care post-ASCT transplant (p=0.2998). Furthermore we were unable to statistically correlate high-risk HCT-CI score with an increased rates of 100-day NRM (p=0.0681) or 1-year mortality (p=0.0656). We further investigated the breakdown of HCT-CI scoring of high-risk pts (n=177). The dominant comorbid conditions that appeared to be driving points towards a high-risk designation was cardiopulmonary (70.5%) and psychiatric (34.5%). Conclusion In our single center experience the categorization of high-risk HCT-CI prior to ASCT did not portend a higher risk with regards to OTI, 100-day NRM, or 1-year NRM when compared to pts categorized as low and intermediate risk in ASCT. A high risk HCT-CI score did not predict for a statistically significant increase in need for higher level of care post ASCT beyond caregiver support.

Positron emission tomographic (PET) scanning with a near-simultaneous computedtomography(CT)scan(ie, integrated PET-CT scan) is the preferred imaging modality for staging lymphomas. PET scanning detects Hodgkin lymphoma as well as the aggressive and most indolent non-Hodgkin lymphomas. PET-CT has become the standardof care for assessment of remission in patients with [F]fluorodeoxyglucose (FDG)-avid lymphomas, including Hodgkin lymphoma. The use of PET-CT scans for restaging is not without pitfalls. Although the sensitivity of a PET scan is nearly 100%, the positive predictive value is lower. We report the case of a woman with a history of Hodgkin lymphoma who was noted to have new lymphadenopathy in a restaging scan, implying progression of the disease. However, on further workup, it was determined that this was not the case.

Proton pump inhibitors (PPIs) are not widely recognized as a cause of drug-induced thrombocytopenia. Literature is mainly confined to case reports and has been insufficient to explore the possibility that this adverse event may be attributed to a class effect of PPI therapy. We present a case where platelet counts dropped from 177 (×10(3) per mm(3)) to 47 (×10(3) per mm(3)) within 6 days after the patient was switched from omeprazole to pantoprazole. There have been case reports of thrombocytopenia caused by PPIs; however, this is noted to be extremely rare. In our case, the patient developed thrombocytopenia on two separate occasions of exposure to pantoprazole, which resolved after stopping the medicine, thus providing definite proof of pantoprazole causing thrombocytopenia. Moreover, the patient did not have thrombocytopenia with omeprazole, thus suggesting that thrombocytopenia with PPIs might be an individual drug effect rather than a class effect. This occurrence has been reported in three other case reports as well. From the nine case reports that we have reviewed, direct causal relationship was found in a few reports only. It has been hypothesized that this adverse effect may be immune mediated, but further investigations are still needed to identify the exact pathogenesis.